Retinoblastoma is a rare malignant tumor of the eye which occurs in children. One third of cases show an autosomal dominant pattern of inheritance. Of the 1200 cases on file at the Institute of Ophthalmology of the Columbia-Presbyterian Medical Center, 20 cases apparently show spontaneous regression of retinoblastoma without treatment, a much higher rate of regression than that observed in other malignancies. One half of these cases are of the familial type with multiple family members affected in more than one generation. In retinoblastoma survivors, however, there is a high incidence of additional primary tumors. We propose to compare the immune response of patients with spontaneous regression of retinoblastoma with the immune response of affected relatives without regression, unaffected relatives, unrelated patients with retinoblastoma and normal controls. Cell mediated cytotoxicity and lymphocyte blastogenic response against retinoblastoma tissue culture lines and control tumor lines will be studied with allogeneic and with autologous serum. The major histocompatibility determinants at the HL-A loci and at the lymphocyte determined MLC loci will be defined. Lymphocyte responses to mitogens and antigens will be determined. We will thus attempt to establish whether or not immune mechanisms play a role in spontaneous regression of retinoblastoma. Similar studies will be carried out in survivors with late appearance of additional primary tumors. This work may help to predict the course of retinoblastoma and provide more effective treatment in the future. Study of this unique malignancy may eventually lead to clarification of mechanisms fundamental to all malignant disease.